Ovarian cancer is the most lethal gynecologic malignancy and the fifth leading cause of death in women. Women with ovarian cancer are typically diagnosed at late stage, when the cancer has spread into the peritoneal cavity and surgical removal is very challenging and incomplete. Five year survival for these late-stage patients is around 30% with recurrent chemotherapy-resistant disease accounting for most ovarian cancer deaths. This contrasts with a 5-year overall survival time of 90% for patients with early-stage disease (Bast et al. (2011) Ann. Oncol. 22 Suppl 8:viii5-viii15; Landen et al. (2008) J. Clin. Oncol. 26:995-1005; Vaughan et al. (2011) Nat. Rev. Cancer 11:719-725). A subset of about 25% of ovarian cancer patients harbor mutations in the BRCA1 or BRCA2 cancer-predisposition genes (Alsop et al. (2012) J. Clin. Oncol. 30:2654-2663; Clamp et al. (2015) Lancet Oncol. 16(1):10-12; Hennessy et al. (2010) J. Clin. Oncol. 28:3570-3576). These patients generally have a more favorable response to chemotherapy and are also candidates for poly-ADP-ribose polymerase (PARP) inhibitors (Clamp et al., supra; Ashworth et al. (2008) J. Clin. Oncol. 26:3785-3790; Sonnenblick et al. (2015) Nat. Rev. Clin. Oncol. 12:27-41; Underhill et al. (2011) Ann. Oncol. 22:268-279; Ledermann et al. (2014) Lancet Oncol. 15:852-861; Oza et al. (2014) Lancet Oncol. 15(11):1207-1214). As such sequencing a buccal wash or blood sample from patients is a companion diagnostic for deciding whether or not a patient will receive a PARP inhibitor as part of their therapeutic regiment (Gunderson et al. (2015) Expert Rev. Mol. Diagn. 15:1111-1116). However, from numerous genomic studies, extensive intra- and inter-tumoral heterogeneity has been documented in both BRCA and non-BRCA ovarian tumors (Cancer Genome Atlas Research Network (2011) Nature 474:609-615; Konecny et al. (2014) J. Natl. Cancer Inst. 106; Patch et al. (2015) Nature 521:489-494; Tothill et al. (2008) Clin. Cancer Res. 14:5198-5208). To date little of the genomic information has been incorporated into clinical decision-making regarding disease management. At present several FDA-approved markers are available for monitoring various aspects of ovarian cancer. For many decades serum levels of MUC16, measured by CA125 antibody, have been used to monitor treatment and disease recurrence. However, over the past 5 years, new tests have been FDA-approved to monitor ovarian cancer treatment and disease recurrence, including serum levels of human epididymis protein (HE4). However, results from several studies report variable values for specificity and sensitivity. In particular, CA125 has typically poor specificity (Leung et al. (2014) Adv. Clin. Chem. 66:25-77). In summary, these tests, while of some clinical utility, can be unreliable.
Therefore, identification of reliable biomarkers for early ovarian cancer detection, monitoring treatment, as well as for predicting time to relapse is urgently needed to improve survival rates.